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Pathwork First to Net FDA OK for Cancer of Unknown Primary Dx

By being the first to launch an FDA- and CLIA-approved test designed to help physicians determine cancer type in a tumor, Pathwork Diagnostics may have gained a significant advantage over competitors.
Last week, Pathwork received 510(k) clearance from the FDA for its Tissue of Origin test.
The test, which uses Pathwork’s PathChip microarray and runs on Affymetrix’s GeneChip platform, “is the first custom Affymetrix gene expression array to be cleared for diagnostic use,” the FDA noted in a statement.
Pathwork is not the only company with a diagnostic test for cancer of unknown primary origin. Currently, AviaraDx markets a CUP assay in the US, called Aviara CancerTYPE ID, which Agendia markets in Europe as CUP-Print. AviaraDx plans to also submit its test for FDA clearance in the next 12 to 18 months.
Meanwhile, Rosetta Genomics and Exiqon are both developing a diagnostic for the indication.
However, Pathwork’s product is the only test that is FDA-cleared for CUP, and its regulatory approval also marks an achievement for the agency. The Tissue of Origin test is only the second in vitro diagnostic multivariate index assay to receive the FDA’s approval. 
The FDA has said that it intends to regulate so-called IVDMIAs, a subset of laboratory-developed tests that combine multiple variables into a single, predictive test, and has issued two draft guidances in this regard. The first IVDMIA to receive a nod from the FDA was Agendia’s MammaPrint assay for breast cancer recurrence [see PGx Reporter 08-01-2007]. 
According to the National Cancer Institute, between 2 percent and 4 percent of US cancer patients have a cancer for which the primary site is never identified. Pathwork claims that as many as 200,000 newly diagnosed cancer patients in the US can benefit from the Tissue of Origin test.
For patients in whom the primary site of the cancer is eventually found, the lung and pancreas are the most common primary cancer sites, but CUP has also been traced back to the breast, prostate, colon, or rectum. Identifying the primary site of cancer allows doctors to more effectively treat the disease in patients.
David Craford, Pathwork’s VP of commercial operations, told Pharmacogenomics Reporter this week that “the cost to identify a primary tumor can be significant,” since traditional treatment approaches involve running multiple diagnostic technologies in parallel.
As early as in 1995, Schapira et al. published an article in the Archives of Internal Medicine that found that unknown primary carcinomas account for between 10 percent and 15 percent of the patients with cancer who present to medical centers. The average cost of diagnosing a patient with CUP at the time was $17,973, and in the study, mean survival was 8.1 months.
“This clinical scenario is one where attention to outcome, clinical management, and expense should be carefully considered,” the study authors wrote.
Given this, “we feel that the Tissue of Origin test will offer labs a cost-efficient option to help determine the origin of uncertain tumors,” Craford said. 
As the first FDA-cleared product in this market segment that already has CLIA certification, Pathwork’s Tissue of Origin test is a competitive edge in this market segment, according to Sudeep Basu, senior analyst for drug discovery technologies & clinical diagnostics at Frost & Sullivan.
“The competing molecular diagnostic tests in the market in its class do not yet have FDA clearance. There aren’t substantial revenues being made in this segment yet, though the growth potential is fairly high,” Basu told Pharmacogenomics Reporter this week.
“Given that recently, the field has witnessed significant activity with respect to new entrants and ramping up of sales forces by few existing players, it is almost certain that this segment will experience high growth rates between now and 2011,” he noted.
Pathwork’s Test
Pathwork’s Tissue of Origin test is a microarray-based assay that, as an IVDMIA, can simultaneously measure gene expression levels in 1,500 genes. The test has been found to confirm the tissue of origin in 15 common malignant tumor types, including bladder, breast, and colorectal.
According to Craford, the test is indicated for patients whose cancer is found in an unexpected location; in whom tumor cells are poorly differentiated or undifferentiated, making interpretation difficult; and in whom the cancer is found in multiple locations, demonstrating metastatic disease without a clear primary site.
In the clinical validation study of 545 metastatic, poorly differentiated or undifferentiated tumors, which Pathwork submitted to the FDA, the Tissue of Origin test demonstrated 89-percent positive agreement and 99-percent negative agreement with available diagnoses. In a cross-laboratory comparison of 60 metastatic, poorly differentiated or undifferentiated tissue specimens from four labs, the test demonstrated an average of 94-percent overall concordance.
The FDA has assessed that the accuracy of the Tissue of Origin test is “similar to that achieved by expert pathologists using current standards of practice.”
"The clearance of the Pathwork test is another step in the continued integration of molecular-based medicine into standard practice," Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, said in a statement.

“Providing a test as a CLIA-approved test before the FDA approval is received as a beneficial strategy. It helps you to hit the ground running quicker.”

"In the past, scientists have classified different types of cancers based on the organs in which the tumors develop,” Schultz added. “With the help of microarray technology, they will be able to classify these types of cancers in a standardized non-reader-dependent manner, based on the patterns of gene activity in the tumor cells."
Pathwork submitted its application for 510(k) clearance in March, and received the go-ahead from the agency five months later.
In expressing its intent to regulate IVDMIAs, the agency had sent warning letters to a number of diagnostics firms, among them Genomic Health, who is still in discussions with the FDA about the regulatory status of is Oncotype DX breast cancer recurrence test [see PGx Reporter 08-08-2007].
At Frost & Sullivan, Basu has evaluated the current business strategies of players in the molecular diagnostics arena, and found that a dual-pronged strategy for commercialization — that is, securing CLIA certification and then willingly pursuing FDA approval — can improve a test’s chances for market success, enhance its reimbursement potential, and increase investor confidence in the product.
“Providing a test as a CLIA-approved test before the FDA approval is received as a beneficial strategy. It helps you to hit the ground running quicker,” Basu said, adding that this model can help establish a product’s branding and visibility, enable the sponsor to develop an educated sales force, and cultivate relationships with physicians.
FDA approval following CLIA certification “can also help with negotiating the reimbursement environment better, given that some efforts would have been made in that direction already,” Basu noted. “From a higher plane, investor confidence increases in a company that has demonstrated strategic vision, due diligence, and good execution to gain FDA approval.” Basu’s analysis will soon be available through Frost & Sullivan.
The company plans to market the CUP diagnostic service and the IVD kit directly to physicians through trade shows, peer-reviewed publications, webinars, clinical symposium, and presentations at medical institutions around the country. Pathwork will dedicate a direct sales force behind its CUP testing service and kit. However, Craford would not disclose the size of its sales force.
Pathwork will conduct the informatics analysis for the laboratory service, and the clinical report associated with the test will be reviewed and released by a Pathwork laboratory pathologist. For the IVD kit, the informatics analysis will be done by Pathwork, but the data report will be sent to the laboratories that purchased the kits, so that they can issue the final report.
Competition Brewing
Without FDA clearance, AviaraDx’s CancerTYPE ID will be the main competitor to Pathwork’s test.
On AviaraDx’s website, the company describes CancerTYPE ID as an RT-PCR-based assay that uses a panel of 92-genes and is capable of classifying 39 tumor types with an 87-percent success rate. The test is performed on formalin-fixed, paraffin-embedded biopsy material obtained from the patient, as well as small core biopsy samples of tumor tissue. Test results will provide doctors with the top five primary cancer site predictions based on the gene expression of the tumor sample or biopsy.
CancerTYPE ID can identify the primary site of many types of epithelial malignancies, sarcomas, and melanomas, according to AviaraDx. Once the results are delivered, physicians can discuss the results with AviaraDx’s medical director. Results from the test are available within ten working days.
Ultimately, AviaraDx also plans to submit its test to the FDA. “We are further improving our assay to make it even better, more capable of working with extremely small specimens, and we will not submit until we have gotten it to where we want it to be,” a spokesperson for AviaraDx told Pharmacogenomics Reporter this week.
The list price for CancerTYPE ID is $3,350, but with Medicare coverage, the test costs approximately $2,850. Agendia, marketing an older version of AviaraDx’s test in Europe as CUP-Print, charges €2,950 ($4,573) for the test.
Pathwork’s Tissue of Origin Test service will cost $3,750, while the Pathwork Diagnostics Tissue of Origin IVD kit will be priced at $1,875, according to the company.
However, regardless of who makes the CUP assay, comments from both AviaraDx and Pathwork suggest that since tests for this indication are new, insurers will need some convincing regarding reimbursement.
On its website, AviaraDx notes that it is “working directly with providers and payors to provide reimbursement as quickly as possible. 
“Because this test is new, many insurance companies will first evaluate the test and then determine how to set their reimbursement policy,” the company states. “AviaraDx works with patients and third-party payors regarding coverage and reimbursement of the test.
Similarly, Pathwork’s Craford said that the company has begun conversations with payors and anticipates initially the test “will be reimbursed on a case-by-case basis.”
According to Agendia, developer of the first FDA-approved IVDMIA MammaPrint, a combination of the agency’s stamp of approval and additional studies to show the clinical utility of their test has helped spur adoption and reimbursement.
The safety and clinical effectiveness data Agendia submitted to the FDA for MammaPrint’s clearance also provided “a solid basis for reimbursement documentation,” Agendia CEO Bernhard Sixt told Pharmacogenomics Reporter this week. “In addition, since the FDA clearance was granted, Agendia has gathered additional data proving insight into MammaPrint's health economic value. 
“Now that Agendia is well on the way to making MammaPrint widely available across the US and as sales continue to increase, it is our expectation that increased utilization and demand will facilitate our current reimbursement efforts,” Sixt added.
While the FDA has not stipulated any post-marketing studies for Pathwork, the company is in the process of conducting a number of studies to demonstrate benefits for running the test.
Soon to Come
There are at least two other CUP diagnostics currently under development.
Rosetta Genomics has said it is developing a test for the indication, which the company hopes to validate and submit for regulatory approval by the end of this year.
As reported in Pharmacogenomics Reporter sister publication RNAi News, Rosetta published data in Nature Biotechnology showing how a collection of 48 miRNA signatures could be used to pinpoint the origin of cancers of unknown primary with around 90 percent accuracy, using a proprietary classification algorithm [see RNAi News 3-27-2008]. 
In May, Exiqon announced it had received a $3 million grant from the Danish National Advanced Technology Foundation to continue developing a microRNA-based diagnostic for identifying the source of cancers of unknown primary origin. However, the company said it doesn’t plan to introduce a CUP diagnostic until 2010.

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